This invention relates to a method and composition for increasing blood pressure in a patient having low blood pressure.
It is well known that the neurotransmitter norepinephrine is derived from dihydroxyphenylalanine (DOPA). DOPA is, in turn, produced in neurons by the enzymatic hydroxylation of the amino acid tyrosine. This process is catalyzed by the enzyme tyrosine hydroxylase. The DOPA is decarboxylated to dopamine by the enzyme aromatic L-amino acid decarboxylase (AAAD) and norepinephrine is produced from dopamine in neurons that also contain this reaction chain, the rate-limiting step is the conversion of tyrosine to DOPA. Drugs that act by increasing norepinephrine levels in synapses include the Monoamine Oxidase Inhibitors (which slow the destruction of these neurotransmitters) and the tricyclic antidepressants; these compounds, which are used in treating diseases like depression; also relatively non-specific-producing many chemical effects besides increasing synaptic norepinephrine levels-and thus have a range of unwanted side effects such as the dangerous increases in blood pressure that occur when people receiving monoamine oxidase inhibitors eat certain foods.
Other diseases appear to be caused by the presence of excessive quantities of norepinephrine within synapses including hypertension and cardiac arrhythmias (too much norepinephrine released from sympathetic neurons). These diseases now usually are treated by drugs that block the interactions of norepinephrine with their post-synaptic receptors. However, these agents all exhibit some non-specific actions as well, and thus cause side-effects.
Prior attempts to increase or decrease the levels of dopamine or norepinephrine by modifying neuronal tyrosine levels had been deemed unsuccessful because the total amounts of these compounds in brains and tissues were not noted to change. It was first observed in Wurtman et al (Science 185:183-184, July 12, 1974) that increases in brain DOPA concentrations, which, under the conditions of the experiments varied in proportion to the rates at which dopamine and norepinephrine were being synthesized could be obtained by increasing brain tyrosine concentrations, and that decreases in brain DOPA concentrations could be produced by giving rats treatments that decreased brain tyrosine. An example of a treatment that increased brain tyrosine was the administration of tyrosine itself; an example of a treatment that decreased brain tyrosine was the administration of one of the other neutral amino acids, e.g., leucine, that competes with plasma tyrosine for uptake into the brain. Prior to that disclosure, it had been believed that the rate-limiting enzyme, tyrosine hydroxylase, was so saturated with tyrosine, that increases or decreases in brain tyrosine levels would not affect tyrosine's conversion to DOPA. In neither the above Wurtman et al article nor a subsequent paper by Gibson and Wurtman (Biochem. Pharmacology, 26:1137-1142, June, 1977) was it actually shown that such changes in DOPA accumulation were accompanied by changes in brain dopamine nor norepinephrine levels. Furthermore, in neither was it shown that changing brain tyrosine levels had any effect on the amounts of dopamine nor norepinephrine released into synapses.
It has been disclosed by Laborit et al in Agressologie 1969, Vol. 10, No. 3, pp. 199-215 that animals can be treated for hemorrhagic shock with the combination of tyrosine, chloropromazine and a compound having an SH group or a combination of tyrosine and chloropromazine in order to reduce fatalities. The results set forth in this article also are disclosed in U.S. Pat. No. 3,651,237, issued Mar. 21, 1977. There is no disclosure in these references wherein the person skilled in the art would relate the administration of tyrosine to cause an increase in blood pressure, inasmuch as (a) no data were provided on blood pressures, and, (b) the authors stated that the ". . . arterial hypotension . . . is insensitive to the therapy described." The inventor named in U.S. Pat. No. 3,651,237 has reported in Aggressologie, 1970, Vol. 11, No. 2, pp 139 to 151, and in Aggressologie, 1969, No. 3, pp 241 to 248 that the administration of tyrosine causes a reduction in blood pressure (after stimulation of the vagus nerve). We believe that it would be a mistake to use chlorpromazine along with tyrosine in situations where it is desired to increase blood pressure, inasmuch as this drug blocks certain catecholamine receptors, and can itself lower blood pressure.
It would be highly desirable to provide a means for increasing the amounts of norepinephrine that actually are present within synapses. Such changes in synaptic transmitter levels need not be associated with changes in the total amounts of norepinephrine present in the brain or other tissues, inasmuch as it is now well known that not all of the molecules of the transmitters that are stored in neurons are equally accessible for release into synapses. More specifically, it would be desirable to provide a means for increasing release of norepinephrine in sympathetic neuronal synapses in order to treat conditions to a disease associated with dangerously low blood pressure.